Exciting new research published in Nature Communications cites using HemaCare leukapheresis material to design primary human T cells that may be more effective at fighting cancer than CAR-T cells. 
The successful treatment of B cell leukemias with genetically modified T cells heralded a new frontier in cell-based medicines. CAR-T cells, or chimeric antigen receptor T cells, have become the face of cell and gene therapy, with Novartis’ first-in-class Kymriah® prompting a robust pipeline of competitive CAR-T treatments. Now a research group in Cambridge, Massachusetts is taking T cell-based immunotherapy one step further. By changing the way T cells target cancer cells, they claim to have come up with a more effective cancer immunotherapy mechanism.
Approved CAR-T therapy treatments recognize cancer cells by interacting with CD-19, a biomarker for B cell development. The marker can be used to tag cancerous “blast” cells in leukemia patients. During CAR-T manufacturing, patient-derived T cells are modified to express a surface receptor targeted to CD19. Once this receptor binds its target on a cancer cell, that cell is destroyed. While this works remarkably well against some blood-borne cancers, it isn’t effective against solid tumors, and can provoke potentially dangerous side effects.
TRuC (T cell receptor fusion construct) therapy uses a different approach. The authors surmised that if they could fuse the CD19 targeting function to a T cell’s TCR (T cell receptor) complex, they might be able to circumvent many of the drawbacks of both CAR-T and TCR-based cancer immunotherapies.
Primary human T cells were isolated from leukapheresis products purchased from HemaCare. HemaCare’s strict quality standards ensure consistently pure, viable, and functional cells; attributes which are essential to a high-quality final product. The authors used the same CD19 antigen receptor sequence used to manufacture FDA approved CAR-T therapies. Following T cell isolation, scientists constructed five distinct TRuC variants, each with the CD19 receptor incorporated into different positions on the TCR complex. Each construct was investigated for its ability to display TCR-like signaling upon activation of the modified T cells.
Unlike CARs, TRuCs are designed to be an integral part of a fully functional TCR complex, rather than a stand-alone receptor. The Cambridge researchers were able to confirm successful TCR integration through a series of experiments. They also showed that all five CD19-specific TRuCs could activate T cells upon interaction with CD19-expressing target cells. The ability of the TRuC-T cells to bind and destroy their target cells was equivalent or superior to CD19-expressing CAR-T cells. Furthermore, in mouse xenograft models the TRuC-T cells showed greater efficacy against solid tumors than CAR-Ts. They also show significantly lower cytokine release, suggesting that treatment could have fewer dangerous side effects. Finally, TRuCs function in an HLA-independent manner, potentially circumventing the need for HLA-matching in patients.
This innovative new T cell therapy has yet to be tested in humans, but if the promising results seen in this breakthrough study are borne out, scientists may well have discovered an even more effective tool in the fight against cancer.
- Baeuerle P.A., e al. Synthetic TRuC receptors engaging the complete T cell receptor for potent anti-tumor response. Nature Communications. 10(2087) 1-12, April 2019.